The present invention relates to a method for synthesizing C-glycosides of ulosonic acids, as well as intermediates thereof and particular C-glycosides prepared by the method.
xcex1-O-glycosides of N-acetylneuraminic acid (Neu5Ac, 1, Scheme 1) are often found terminating the oligosaccharide component of cell-surface glycoproteins and glycolipids. Neu5Ac is involved in a number of important biological events: intercellular interactions such as adhesion, aggregation and agglutination; masking of antigenic oligosaccharides and suppressing undesired immune reactions (antirecognition phenomena); influencing the cell membrane permeability for permeability for ions, amino acids and proteins; and protection of glycoproteins against proteolysis1. Terminal Neu5Ac is an attachment site of pathogens to the cells and often catabolic and inflammatory processes are initiated on the removal of this carbohydrate group2. In general the xe2x80x9crightxe2x80x9d life time of a cell is a reflection of a delicate balance between the introduction and removal of terminal Neu5Ac or other sialic acids.
The glycosidic bond of Neu5Ac is cleaved in vivo by hydrolase type enzymes, called neuraminidases3. Therefore, designing nonhydrolyzable analogs of Neu5Ac-xcex1-O-glycosides is an attractive approach to control, at the molecular level, events of crucial importance to glycobiology and immunology. The replacement of the interglycosidic oxygen atom by a methylene group, for example, generates a class of hydrolytically and metabolically inert isosteres, the Neu5Ac C-glycosides. Despite several elegant methods for direct carbon-carbon (Cxe2x80x94C) bond formation at the anomeric center in aldoses and ketoses4, no major advances have been reported in the synthesis of Neu5Ac C-glycosides5. The major problem confounding their synthesis is the requirement that the Cxe2x80x94C bond being formed results in a quaternary C-atom.
Accordingly, an object of the present invention is to provide a method for synthesizing C-glycosides of ulosonic acids such as Neu5Ac, by which diastereocontrolled synthesis of xcex1-C-glycosides of ulosonic acids is attained. Another object of the present invention is to provide intermediates of the novel method, and to provide novel C-glycosides of particular ulosonic acids, which are synthesized by the novel method.
The present inventors intensively studied to discover that diastereocontrolled synthesis of xcex1-C-glycosides of ulosonic acids is attained by carrying out the reaction between ulosonic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide such as SmI2, thereby completing the present invention.
That is, the present invention provides a method for synthesizing C-glycosides of ulosonic acids comprising the step of reacting an ulosonic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
Preferably, the lanthanide metal halide of the invention is a halide of samarium (II).
The present invention also provides a method for synthesizing C-glycosides of carbohydrates containing a quaternary carbon comprising the step of reacting said carbohydrate with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of neuraminic acids or sialic acids comprising the step of reacting the protected neuraminic acid or sialic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of KDO comprising the step of reacting the protected KDO sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of KDN comprising the step of reacting the protected KDN sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a samarium III adduct of ulsonic acids. The present invention still further provides a samarium III adduct of ulsonic acids.
The present invention still further provides a samarium III adduct of carbohydrates containing a quaternary carbon. The present invention still further provides a samarium III adduct of neuraminic acids or sialic acids. The present invention still further provides a samarium III adduct of 3-deoxy-D-manno-octulosonic acid. The present invention still further provides a samarium III adduct of 2-keto-3-deoxy-D-glycero-d-galactonononanoic acid.
The present invention still further provides C-disaccharide having the structure, methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-2-C-{(S)-hydroxy-[3-(methyl-2,4,6-tri-O-benzyl-3-deoxy-xcex1-D-galactopyranosidyl)]-methyl}-D-erythro-L-manno-nonanate. The present invention still further provides C-glycoside having the structure, Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-2-C-{hydroxy-4-(tert-butylcyclohexyl)]-D-erythro-L-manno-nonanate.
By the present invention, diastereocontrolled synthesis of xcex1-C-glycosides of ulosonic acids is first attained, and novel intermediates and C-glycosides of ulosonic acids were provided.